The Baltimore Longitudinal Study of Aging (BLSA), the major research program on human aging supported by the Intramural Research Program of the NIA, was established in 1958 and conducted at the Gerontology Research Center through 2003. Beginning in 2003 a new research unit was established at Harbor Hospital (Baltimore). The study continues to represent a consortium of scientists who work collaboratively to characterize normal and pathological aging. The current team of researchers directing the BLSA has implemented major changes in its design and assessment technology. The primary scientific goals remain consistent with the original BLSA legacy to: 1) identify age-associated differences among individuals that are not explained by diseases and 2) characterize factors that affect transitions from normal to pathological aging. New measures have and continue to be implemented aimed at gaining a better understanding of the effect of age and diseases on the process that leads to mobility disability and poor quality of life in many older adults. Using an integrative and multidisciplinary approach, the study aims to identify and delineate the compensatory mechanisms that occur at multiple levels (cells, tissues, organs, whole body, society) that allow many older persons to maintain a high level of mobility, in spite of multiple pathological processes. The study population consists of a cohort of volunteers followed for life over multiple follow-up visits. Many participants have been enrolled in the study for over 20 years, and some for as long as 45 years. The study is currently enrolling individuals 80 years and older who are extremely well-functioning and have exceptional health. This new aspect of the BLSA has been named The IDEAL (Insight into the Determinants of Exceptional Aging and Longevity) Study. Historically, the BLSA has been the gold-standard reference for aging-related changes in multiple systems. Important findings in cardiovascular function over the life course, factors affecting risk of prostate cancer, age-associated decline in cognitive function, glucose metabolism, muscle strength and bone integrity continue to be published in the present day. Some research goals will be pursued by conducting, in parallel, ancillary studies limited to defined subsets of participants and designed to address pre-formulated hypotheses with the objective of providing information more directly applicable to clinical medicine. The structure of the current BLSA design is based on three levels of measurement: 1. The reference outcome measures are physical and cognitive function. All other measures, directly or indirectly, are aimed at understanding the mechanisms by which old age is associated with high risk of developing mobility disability and impaired cognitive function. Accordingly, the BLSA collects an extensive set of measures on many different aspects of physical and cognitive function; 2. The intermediate level includes measures of anatomical integrity and functionality of the physiological systems important for mobility: central nervous system, peripheral nervous system, muscle, bone and joints, delivery of substances important for energy production, sensory systems that provide feedback from the environment; 3. The third level includes the physiological systems important for maintaining a stable biological homeostasis and include measures of immune function, hormones, oxidative stress/antioxidants, autonomic nervous system, nutritional intake, and physical activity. The overarching hypothesis is that dysfunction of the systems that maintain biological homeostasis is the primary cause of age-associated decline in physical function and development of frailty. Considerable resources have been dedicated to restructuring, documentation and cleaning the data collected over the last 55 years. This project is already in an advanced stage of development andproducing important results concerning clinical features for the diagnosis and prognosis of prostate cancer, secular trends in WBC, body weight, muscular strength and their relationship with mortality over the last half of the century and genetic traits associated with accelerated decline in physical function. An essential part of this plan is the inventory, classification and quality control of the entire collection of biological specimens (urine, blood, serum, plasma, red blood cells, etc) collected in BLSA participants during the entire course of the study. In addition, a wide genome scan (Illumina 550K) has been performed in over 1450 participants with available DNA. Using the rich collection of phenotypes collected over many years and the Illumina genotypes, the BLSA has contributed data to several genetic consortia examining the contribution of genetic variability to different human phenotypes, such as blood pressure, circulating lipids, uric acid, pro-inflammatory markers and many others. In addition, we are starting new work on gene-environment interactions. An important sub-project consists of recruiting a new cohort of exceptionally healthy older persons (IDEAL), examining the cross-sectional characteristics of this group compared to the general population, and measuring several physiological parameters that may be directly or indirecly connected with physical and cognitive function. From this prospective, the future plan for the BLSA is to become a permanent laboratory of physiology that studies the different physiological changes that occur over the aging process, with the final aim of understanding their inter-relationships and describing the mechanisms by which they contribute to maintenance of homeostatic equilibrium. Since many BLSA participants who become sick and disabled were often unable to come to the Baltimore clinic for a traditional visit in the clinic creating a severe ascertainment bias informative censoring) in the study of age-related outcome the BLSA has started a home visit project aimed at collecting information from individuals that are no longer able to come to the Baltimore Clinic for their traditional visit. This portion of the project is handled through a R&D contract mechanism described in another report.